How to shoot the messenger

Jan 26, 2010
This image shows the three-dimensional structure of death-associated protein kinase (green and yellow) when bound to calmodulin (violet and blue). It was obtained by X-ray crystallography. Credit: Mathias Wilmanns/EMBL

Cells rely on a range of signaling systems to communicate with each other and to control their own internal workings. Scientists from the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, have now found a way to hack into a vital communications system, raising the possibility of developing new drugs to tackle disorders like neurodegeneration, cancer and cardiovascular disease. In a study published today in Science Signaling, they have pieced together the first snapshot of what two of the system's components look like while interacting.

One way these signalling systems work is by triggering a flood of inside the cell. These get picked up by a receiver, a protein called calmodulin which turns this calcium signal into action by switching various parts of the cell's machinery on or off. Calmodulin regulates a set of proteins called kinases, each of which controls the activity of specific parts of the cell, thus altering the cell's behaviour.

Using high-energy X-rays produced by the (ESRF) in Grenoble, France, and by the German Synchrotron Radiation Centre (DESY), in Hamburg, Germany, Matthias Wilmanns' team at EMBL revealed the molecular structure of one of these kinases, a protein called Death-Associated DAPK, when bound to calmodulin. The structure showed how calmodulin binds to a particular section of DAPK, switching the kinase on so that it can go and change the function of its targets. The team then worked out which of DAPK's building blocks, or , were crucial for calmodulin to bind.

"Faulty versions of DAPK are involved in the development of some cancers," says Wilmanns, "so we want to know more about how this functions to allow its better exploitation as an anti-cancer target."

What's more, DAPK has physical similarities to many of the other kinases controlled by calmodulin, meaning many of them are likely to interact with calmodulin in the same, or similar ways. Being able to see the three-dimensional structures of these proteins, how they clip together and alter each other's behaviour means researchers can devise ways to manipulate this interaction with drugs.

"That will provide a platform to get into drug discovery," says Wilmanns, adding, "obviously, this is the beginning of the story." He is planning to do so in an ongoing collaboration with Adi Kimchi's team at the Weizmann Institute in Israel and other groups from EMBL.

Explore further: Researchers create designer 'barrel' proteins

add to favorites email to friend print save as pdf

Related Stories

Like eavesdropping at a party

Jul 31, 2008

Cells rely on calcium as a universal means of communication. For example, a sudden rush of calcium can trigger nerve cells to convey thoughts in the brain or cause a heart cell to beat. A longstanding mystery has been how ...

Squeeze play: Protein's grip like a baseball bunter's

Oct 10, 2006

Like all good baseball players, the protein calmodulin appreciates the importance of maintaining a good grip. A vital regulatory protein in all plants and animals, calmodulin is known to grab hold of hundreds of different ...

Yale scientists map cell signaling network

Nov 30, 2005

Yale University scientists have mapped, for the first time, the proteins and kinase signaling network that control how cells of higher organisms operate.

Recommended for you

Researchers create designer 'barrel' proteins

4 hours ago

Proteins are long linear molecules that fold up to form well-defined 3D shapes. These 3D molecular architectures are essential for biological functions such as the elasticity of skin, the digestion of food, ...

World's fastest manufacture of battery electrodes

10 hours ago

New world record: Scientists at the Karlsruhe Institute of Technology (KIT) increased the manufacturing speed of electrode foils coated batch-wise by a factor of three – to 100 meters per minute. This was ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

stealthc
not rated yet Jan 26, 2010
protein folding is only just getting understood and is probably a system not only worthwhile examining for new drugs, it is a system worthwhile looking at because of the scale at which it operates it holds further clues to quantum phenomena.